IOTA is a partner in the EU initiative to discover drugs for Neglected Parasitic Diseases, PDE4NPD, which focusses on phosphodiesterases as therapeutic targets in parasitic diseases.

The PDE4NPD programme has developed and published a range of pharmacological tools which have validated specific PDEs as therapeutic targets in trypanosomiasis.

PDEs in human drug discovery

There are 11 subtypes of human phosphodiesterases, many of which are proven disease targets. Of particular interest are PDE10A which population studies have implicated in schizophrenia, PDE5 which is the molecular target of the erectile dysfunction drug Sildenafil, and PDE4 which is the target of the anti-inflammatory drug Roflumilast. The role of specific PDEs in regulating intracellular signalling and physiological function is an area of burgeoning importance.

IOTA’s drug discovery programmes use fragment-based chemical biology approaches to explore structure-function relationships across target gene families, including the PDEs. Shown below, left is an IOTA fragment occupying the active site of a PDE. Shown below, right is a comparison of the selectivity pockets of the trypanosome PDEB1 and human PDE10A.